Document Detail

Effects on promoter activity of common SNPs in 5' region of GABRB3 exon 1A.
MedLine Citation:
PMID:  22765836     Owner:  NLM     Status:  MEDLINE    
PURPOSE: The β3 subunit of the γ-aminobutyric acid type A receptors (GABA(A) -Rs) is an essential component of GABA(A) -Rs in fetal, perinatal, and adult mammalian brain. Various transcripts of the β3 subunit gene (GABRB3) produce various proteins with different N-termini. Rare variants in this N-terminus (exon 1A and exon 2) of GABRB3 protein segregate in affected family members of two multigeneration-multiplex families with remitting childhood absence epilepsy (rCAE), suggesting GABRB3 is a major Mendelian epilepsy gene for rare families with CAE. Therefore, the N-terminus of GABRB3 could be important for GABRB3 regulation in development, and its alteration could produce rCAE. Herein we determine if single nucleotide polymorphisms (SNPs) within the 1,148-bp region upstream from exon 1A influence the expression of GABRB3.
METHODS: We studied luciferase reporter expression for promoter activity, 1,148-bp upstream from exon 1A, using human embryonic kidney 293 cells. We generated constructs of the promoter region and compared different SNP haplotypes in 48 patients with rCAE. Next, we compared frequencies of rs20317, located in the core promoter region, and rs4906902, located in the enhancer region between 48 patients with rCAE and >500 healthy controls matched for ethnicity and ancestral origin.
KEY FINDINGS: Highest luciferase expression occurred 230-bp upstream of exon 1A. The construct that excluded this region lost luciferase activity. Therefore, this region contains the core promoter of exon 1A. Allele C but not allele G (rs20317) significantly increased luciferase expression activity. Allele C creates binding motifs for cMYB and EGR-3. Longer constructs overlapping this region have a binding motif for REST (RE1-silencing transcription factor), a critical epigenetic modulator for neuronal genes. REST represses expression of neuronal genes in nonneuronal tissues, resulting in reduced luciferase expression activity. Even in the suppressed condition, the longer construct enhanced luciferase expression activity of the shorter construct, which excluded the distal end containing rs4906902. However, allele frequencies of rs20317 and rs4906902 were not significantly associated with 48 rCAE patients in comparison to >500 controls matched for ethnicity and ancestral origin.
SIGNIFICANCE: Common SNPs in the promoter region increase luciferase expression activity. An epigenetic modulator, REST, specifically alters expression of GABRB3 exon 1A transcripts, suggesting epigenetic regulation by REST dominantly controls the expression of GABRB3 variant 2 transcript in early life GABA(A) signaling. Abnormal epigenetic regulation could be involved in absence seizures.
Miyabi Tanaka; Julia N Bailey; Dongsheng Bai; Yumiko Ishikawa-Brush; Antonio V Delgado-Escueta; Richard W Olsen
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2012-07-05
Journal Detail:
Title:  Epilepsia     Volume:  53     ISSN:  1528-1167     ISO Abbreviation:  Epilepsia     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-08-13     Completed Date:  2012-10-26     Revised Date:  2013-12-05    
Medline Journal Info:
Nlm Unique ID:  2983306R     Medline TA:  Epilepsia     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1450-6     Citation Subset:  IM    
Copyright Information:
Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.
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MeSH Terms
Epilepsy, Absence / genetics
HEK293 Cells
Luciferases / metabolism
Polymorphism, Single Nucleotide / genetics*
Promoter Regions, Genetic / genetics*
Receptors, GABA-A / genetics*
Repressor Proteins / genetics
Grant Support
Reg. No./Substance:
0/GABRB3 protein, human; 0/RE1-silencing transcription factor; 0/Receptors, GABA-A; 0/Repressor Proteins; EC 1.13.12.-/Luciferases

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